Abstract
In a regulatory first, the FDA has collaboratively reviewed a new cancer treatment with drug agencies in Canada and Australia, allowing for simultaneous approval of lenvatinib in combination with pembrolizumab for the treatment of recurrent endometrial carcinomas.
In a regulatory first, the FDA has reviewed a cancer treatment with drug agencies from around the world, leading to simultaneous approvals in three countries.
The FDA joined Australia's Therapeutic Goods Administration and Health Canada in granting conditional approval in September to lenvatinib (Lenvima; Eisai) plus pembrolizumab (Keytruda; Merck) for recurrent endometrial carcinomas that are not microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR).
The approvals came 3 months prior to the FDA's target decision date—and likely much earlier than would happen otherwise in Australia or Canada, where drug launches often lag a year or more behind those in the United States.
The regulatory bodies came to the shared decision as part of Project Orbis, an initiative of the FDA's Oncology Center of Excellence.
“This is a really important direction,” says Frances Richmond, PhD, chair of the Department of Regulatory and Quality Sciences at the University of Southern California in Los Angeles. Having each agency independently review submissions is redundant “when they're essentially working from the same songbook,” she notes. “The more they can do to reduce the timeline and the cost of [developing] these drugs is a good thing.”
Since 2004, members of the FDA's oncology and hematology division have routinely held conference calls with their counterparts in Europe, Japan, and elsewhere. These virtual meetings have allowed the agencies to share confidential information about ongoing reviews and to identify any regulatory divergences across regions.
As highlighted in an August report from members of the FDA and European Medicines Agency (EMA), such exchanges provide “a form of peer review among fellow regulators,” allowing “for more informed regulatory decision-making, and oversight of regulated industry in areas like inspections and data integrity.” (Clin Pharmacol Ther 2019 Aug 26 [Epub ahead of print]).
Yet, the various agencies involved in these strategic partnerships had never synced the submission, appraisal, or approval of any marketing applications.
Through Project Orbis, review teams from Australia, Canada, and the United States collectively considered data from a phase II trial of 94 women with MSI-H/dMMR–negative endometrial tumors that had progressed following at least one systemic therapy.
In the single-arm study, participants received daily oral doses of lenvatinib, a multikinase inhibitor of VEGFRs and FGFRs, and infusions of pembrolizumab, a PD-1–targeted checkpoint inhibitor, every 3 weeks until unacceptable toxicity or disease progression. The objective response rate was 38%, with 10 patients experiencing complete responses and another 26 exhibiting partial tumor shrinkage. The benefit was generally durable, lasting 6 months or longer in 69% of responders, with a safety profile comparable to that reported previously for both drugs as monotherapies.
A randomized phase III trial evaluating the lenvatinib–pembrolizumab regimen against chemotherapy is currently enrolling patients. Continued approval of the drug combination in all three countries could rest on survival data from this 780-person study.
For now, Project Orbis will primarily consider expanding marketing authorization of new indications for previously approved agents. According to the FDA, future collaborative reviews may involve novel therapies—although because more proprietary information would be involved, sharing data becomes trickier. Future efforts could also involve the EMA, Japan's Pharmaceuticals and Medical Devices Agency, and Switzerland's Swissmedic.
Jon Roffman, MBA, head of oncology strategy at the consulting firm ZS in Boston, MA, welcomes the launch of Project Orbis. “The regulatory process, in aggregate across participating countries, will be strengthened by collaboration and knowledge-sharing among multiple regulatory agencies,” he says.
However, “a significant open question is whether or not reimbursement processes can keep pace with regulatory approval.” –Elie Dolgin
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